Project Summary Abstract The majority of human immune deficiency virus 1 infected patients in the US are on long-term (10+ years) combination antiretroviral therapy (cART). While cART suppresses HIV replication to below 50 copies/ml, not much is known about the long-term effect of cART on Kaposi sarcoma associated herpesvirus (KSHV) oral transmission, oral and systemic KS disease or the latent KSHV reservoir. We propose to investigate the impact that different cART components have on KSHV and KS disease with the long-term aim to interrupt oral KSHV transmission and cure the virus from persons living with HIV/AIDS. Specifically, we will focus on modulating the reactivation of KSHV and how cART drugs affect KSHV exosomes/ extracellular vesicles. This is a competitive renewal application in response to PA-16-426/ High or Medium Priority AIDS Research on Non-AIDS-defining or AIDS-defining Cancers (R01).